Methxleneamino-eyrazolone



Patented Feb. 28, 1950 UNITED v, STATES, PATENT OFFICE companyNoDrawing. Application May-1 5, 1 946, Serial No; 670,042. InFraneeJanuary'18', 1944 Section 1, Public Law 690, August 8, 1946 Patentexpires January 18, 1964 Claims, (01. 260-310 This. invention is: formprovements. in or. re.- lating-to the production of pyrazolonederivatives and, in particular, concerns the preparation of1.-pheny1.--2:3,-dimethylr4 di'methylaminopyra: zolone, also known,under the name pyramr idone, from a new.- i'ntermediate, the.corresponding 4-methyleneaminocompound. This invention also. includes.the. said. intermediatev and processes for theprepa'ration of. the same.

The. preparation. of pyramid'one, (l-phenylL-Z; 3- dimethyl'. 4.dimethylaminopyrazolone or d1.

methyl'amino antipyrine). has heretofore usually" been effected by thedi'methylation of aminoantipyrine, employed. either in the pure stateor} Without. isolation from the medium. inv which it: is.

formed. If'it wasnecessary to isolate theami'n'oantipyrine, which isvery soluble. iniwatenfthe process has become complicated. If" theamino.- antipyrine was dimethyl'ated directly in the solution in whichit was prepared, then most of the impuritieswhichaccompanied itwereretainedzby the pyramidonenin. addition to those. which were formed.during, the. methylation; moreover theaminoantipyrine. solution wasoften sov dilute that;

dimethylation was difii'cult.

. As a result of research.and experiinentation it.

has. now been foundv that, it ispossible to separatethe aminoantipyrinein an, insoluble form from. the medium in whichait has. been.

epared; by combining it with. an equimolecul'ar. 'mount. of'formaldehyde. The compound thus iormed;

For. convenience, the product. is described here.-

inafter as methylene-aminoantipyrine.

When an aqueous solution of aminoantipyrine is treated with a molecular.proportion of formaldehyde: (in the form of the ordinary aqueoussolution); the mixture; which is atfirst clear, becomes more. and moreturbid and a thick, viscous, sticky oil separates. Tnis oil is. slightlysoluble in Water and in alkali, but is soluble in dilute acids,.alcoholsor other solvents. This 011, which is probably methyleneaminoantipyrinein its monomeric form, polymerises more or lessrapidly to: a. solid,product soluble in acids but insoluble in water and sparingly soluble inthe ma ority of. organic solvents inthe cold. It melts atapproximately169-172 C.

The. methyleneaminoantipyrine can therefore be. separated either in theform. or" an oil or in.

the form of a solid. It is di'mcult to enect separation in the form ofan 011 because the latter is sticky and viscous. However, forseparation, use can be made. or thesubstances property of being-stablem-the presence of ausalies and or dissolving readily in benzene andother organic Solvents; The methylenev aminoantipyrihe is more solublein benzene, than is, for example, aminoantipyrine but since it is. less50111019 in Water, it can readily be separated in thei'orm. of asolution in benzene. If the benzene solution is evaporated rapidly invacuo the methyleneaminoantipyrine; is obtained in the form or? the oil.On the other hand, if. thesolution is boiled for some. timev t en there.is. precipitated a solid. product- (polymer) melting, at lbs-172 C. Onkeeping itin the coldior some time it again deposits in asolid form.

It has been foundv that this polymerisation is considerably acceleratedwhen the monomer is stirred in the presence of water and benzene (orsome. other'solvent of. the. monomer'whichis also immisciblewith water).Hence, ii an aqueous solution of formaldehyde is run into an aqueoussolution of aminoantipyrine and stirred with benzene (or with toluene,etc.) it soon forms a 5 cream which becomes completely homogenous.

on removal of the benzene or its equivalent, either by distillation orby evaporation in a current. of gas, there. is formed an aqueoussuspension of polymerised Inethyleneaminoantipyrine, which can befiltered.

The monomeric methylenearninoantipyrine, which isslightly soluble inwater, is soluble in alcohols (methyl, ethyl, etc.) and equally solublein presence of a molecule of aqueous formaldehyde solution. Themethyleneaminoantipyrine of M; P. 169-172 6., is insoluble in water,very slightly soluble in most organic solvents in the or with hydrogenin the presence of a metal hydrogenation catalyst palladium).

Mono-methylaminoantipyrine can in its turn be methylated todimethylaminoantipyrine (pyr-amidone) either by means of a methyl halideor of dimethyl sulphate or, again, of formaldehyde in presence of areducing agent (zinc and hydrochloric acid, formic acid, or hydrogen anda catalyst).

Methyleneaminoantipyrine, polymerised or not, can be converted directlyinto dimethylaminoantipyrine (pyramidone) without isolating themonomethyl derivative, by treatment with a molecular proportion offormaldehyde in the presence of a reducing agent (metal plus an acid, orformic acid or hydrogen in the presence of a catalyst such, for example,as platinum, palladium or nickel).

The present invention is illustrated by the following, non-limitativeexamples in which the parts stated are parts by weight. Of theseexamples, I to VIII illustrate the preparation of the methyleneaminoantipyrine, while the remainder illustrate the preparation ofpyramidone from the methyleneaminoantipyrine.

(nickel, platinum or Example I 203 parts of aminoantipyrine aredissolved in water: 100 parts of a 30% by volume solution offormaldehyde are added to the solution thus formed, either with orwithout stirring: there is soon precipitated an insoluble, more or lessthick and viscous oil, the required methyleneaminoantipyrine.

Example II Following the procedure of Example I, except that the waterin which the aminoantipyrine is dissolved is made alkaline with asolution of an alkali such, for example, as sodium carbonate or causticsoda or caustic potash. When all the formaldehyde has been added,benzene is added (100 parts or more); the oil formed is thereby taken upinto the benzene and the benzene solution is then decanted off. Rapidevaporation of this solution gives the methyleneaminoantipyrine, whichcan then be isolated in the form of a salt (hydrochloride, sulphate,etc.).

Example III Example IV An aqueous solution containing 203 parts ofaminoantipyrine is added to 200 parts of benzene, the whole beingthoroughly shaken; the temperature is raised to 60 C. and over a fewminutes 1001l0 parts of formaldehyde are added. The temperature is thenraised to boiling point (71-72 C.) the methyleneaminoantipyrine polymerforms very rapidly. The benzene is driven off by gradually raising thetemperature to 80 C. the methyleneaminoantipyrine separates in the formof a powder which is easy to filter.

Example V In this example, the procedure of Example IV is followed,except that the benzene and the formaldehyde are added in the coldduring rapid stirring; the methylaminoantipyrine polymerises and'inpresence of the benzene forms a voluminous spongy mass.

lowed to go to completion for some time (one hour, for example) thebenzene is evaporated by 'pyrine canbe replaced by an aminoantipyrinesolution such as is obtained in the processes for its preparation. If,using such a solution, it is desired to work according to Examples I,III, IV

and V, the liquid would have to be exactly neu- Following the procedureof Example II, withis driven off (for example, by distillation underreduced pressure) and the methyleneaminoantipyrine separates in the formof a powder in aqueous suspension, which is readily filtrable. If theprocedure is carried out using a lesser quantity of benzene (100 partsfor example), a filtrable granular powder is obtained directly. Itretains ben-, zene which can be removed by known methods either beforeor after the filtration.

'tralised; according to Example II, it would be necessary to lixiviatewith more than 1 molecule of an alkali. Examples VI, VII and VIIIillus-" trate such modes of procedure.

Example VI 950 parts of the solution from the hydrolysis ofsulphaminoantipyrine containing 97 g. of hydrochloric acid and 77 g, ofaminoantipyrine per litre are added to 400 parts of water; acidity isneutralised with commercial sodium carbonate until the pH is 6.8 (117parts of soda) 300 parts of benzene are then added and at 30 C., over aperiod of 20 minutes, 30-33 parts Ma 30% by weight commercial solutionof formaldehyde are gradually added with stirring. A cream soon formsand gradually becomes thicker. Stirring is continued for some hours inorder to complete the'reaction. Benzene is then distilled off, underpartial vacuum if desired, the temperature being gradually. raised to apoint not exceeding ;C. The cream is gradually converted to an almostcolourless powder which is filtered and washed with water. 63.5 parts ofmethyleneaminoantipyrine of M. P. 169-172 C. arethereb'y obtained, beingsubstantially the theoretical amount (64.1 parts).

Example VII Working with a solution as described in Example VI, butafter neutralisation with carbonate and addition of benzene, 12 parts ofcaustic soda or 40 parts of 30% sodium carbonate or a correspond ngamount ofany other alkali are added, and the formaldehyde is then runin. In this case, acream is not formed; on standing, the reactionmixtures separates into two distinct layers. The upper, benzene layercontains the monomeric methyleneaminoantipyrine which can be recoveredby evaporation of the benzene or can be polymerised by; boiling thebenzene solution or by stirring it with water, in which case it forms acream whichwo'uld be worked up as in the preceding examples. It can alsobe precipitated The polymerisation is al- Example VIII Proceeding as inExample VI, but with the addition of only 60 parts of benzene instead of300 parts and pouring in the formaldehyde with simultaneous rapidstirring, the product is formed, not as a cream, but separates as asemisolid mass. This mass breaks up into spongy granules which hardenmore and more as polymerisation of the methyleneaminoantipyrine'proceeds. The major portion of the benzene is distilled off by raisingthe temperature of the mixture to 80 C.; the methyleneaminoantipyrinesettles as a powder when it is easy to filter and easy to free, bywashing, from entrained salts.

In all of Examples VI to VIII, the quantity of monomeric or polymericmethyleneaminoantipyrine which is recovered corresponds approximately tothe theoretical amount calculated on the amount of aminoantipyrinecontained in the original solution.

The following examples illustrate the conversion of monoor polymericmethyleneaminoantipyrine into pyramidone by two different methods viz:firstly, hydrogenation to monomethylaminoantipyrine, which in turn ismethylated by known method, and secondly by direct conversion todimethylaminoantipyrine.

Example IX Into a hydrogenation apparatus is charged a solutioncontaining 215 parts of methyleneaminoantipyrine, either polymerised ornot, 500 parts of ordinary alcohol, and 100 parts of a 30% (by weight)formaldehyde solution. On warm ing to 50 C. a clear solution isobtained, which does not deposit a precipitate on cooling. Active nickelis added, air in the apparatus is replaced by hydrogen and stirring isbegun; hydrogen absorption is rapid and takes place in the cold and atatmospheric pressure. Hydrogenation can be effected at elevatedtemperature and under pressure if desired. At atmospheric pressure and atemperature of 20-30 C. with rapid stirring, theoretical absorption ofhydrogen is achieved, the time required varying from 30 minutes to 2hours, according to the method of stirring and the amount of nickelused. The catalyst is then separated from the alcoholic solution ofpyramidone. The solution is concentrated and allowed to crystallise.225-230 parts of pyramidone are recovered therefrom, melting at 106-107C.; the yield is quantitative.

Example X 215 parts of methyleneaminoantipyrine are dissolved in amixture of ice and hydrochloric acid (300 parts of ice to approximately800 parts of 30% hydrochloric acid) 100 parts of 30% formaldehyde areadded. The mixture is stirred and 200 parts of zinc dust 75% (or thecorresponding amount if the titre is diiferent) are added gradually, thetemperature being maintained just below 25 C. The mixture is then raisedto 70 C. to complete the solution of the zinc, after which the mixtureis neutralised and the pyramidone is extracted by known methods. Theyield is excellent, approximating to the theoretical.

The experimental conditions herelnbefore described can be varied betweenwide limits. There can be employed, for example, a different reducingmetal in place of zinc (for example aluminium) and an acid other thanhydrochloric, for example sulphuric acid.

Example XI In order to effect the reduction when the reducing agent isformic acid in accordance with the following equation;

the operation must be carried out in the cold. If the temperature isallowed to rise, the reaction proceeds too rapidly. In the foregoingequation R represents the pyrazolone residue.

215 parts of methyleneaminoantipyrine are dissolved in 200 parts ofwater containing 46 parts of formic acid. This solution is pouredgradually into 110 parts of 30% formaldehyde, 50 parts of water, and 50parts of formic acid, the temperature being maintained at 95 C. Theamount of carbon dioxide which is evolved aifords means of following theprogress of the reaction. When the reaction is completed, the whole ismade alkaline and the pyramidone, which is formed in very good yield, isextracted by known methods.

I claim:

1. A process for the preparation of 1-phenyl- 2:3 dimethyl 4methyleneamino pyrazolone which comprises mixing an aqueous solution of1-phenyl-2 3-dimethyl-4-aminopyrazolone with formaldehyde and separating1-phenyl-2z3-dimethyl-4-methyleneaminopyrazolone from the reactionmixture.

2. A process for the preparation of l-phenyl- 2:3 dimethyl 4methyleneamino pyrazolone wherein an aqueous medium containing l-phenyl-2:3-dimethyl-4-aminopyrazolone is mixed with one molecular equivalent offormaldehyde, the reaction mixture is mixed with a water-immisciblesolvent and agitated and1-phenyl-2t3-dimethyl-4-methyleneaminopyrazolone separated in the formof a solid polymer.

3. Process as claimed in claim 2, wherein the water-immiscible solventis benzene.

4. The polymeric form of 1-phenyl-3-methyl- 4-methyleneamino-pyrazolonewhich melts at ap- Cll l l =0 where n is a positive integer.

MAURICE ERNEST BOUVIER.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 1,531,286 l-lofimann Mar. 31,1925 2,045,588 Dvornikoff June 30, 1936 OTHER REFERENCES Annalen, vol.293, page 62 (1896).

Chemical Abstracts, vol. 38, pp. 1233-1234, citing Skita et al.,Berichte, 753, pp. 1696-1702 (1942).

1. A PROCESS FOR THE PREPARATION OF 1-PHENYL2:3 - DIMETHYL - 4 -METHYLENEAMINO - PYRAZOLONE WHICH COMPRISES MIXING AN AQUEOUS SOLUTIONOF 1-PHENYL-2:3-DIMETHYL-4-AMINOPYRAZOLONE WITH FORMALDEHYDE ANDSEPARATING 1-PHENYL-2:3-DIMETHYL-4-METHYLENEAMINOPYRAZOLONE FROM THEREACTION MIXTURE.
 5. COMPOUNDS HAVING THE FORMULA